Using recombinant factor VIIa in patients who do not have hemophilia has very little proven benefit, researchers reported.

Action Points

Explain that a systematic review and meta-analysis found no significant benefit for therapeutic use of factor VIIa in patients without hemophilia and only modest decrease in transfusion needs for prophylactic use.

Note that the researchers raised questions about the quality of the studies and concluded that off-label use of factor VIIa could not be recommended.

Using recombinant factor VIIa in patients who do not have hemophilia has very little proven benefit, researchers reported.

A systematic review and meta-analysis found slight benefits when the compound was used to prevent anticipated bleeding but no benefit at all when it was used therapeutically, according to Yulia Lin, MD, of Sunnybrook Health Sciences Centre in Toronto, and colleagues.

For either application, there was no significant improvement in mortality or significant increase inthromboembolic events, Lin and colleagues reported online in CMAJ.

The compound is indicated for treatment of hemophilia but is widely used off-label, the researchers reported. Indeed, of the 2,700 patients in the Australian and New Zealand hemostasis registry, they noted, only 1% have hemophilia.

Because of such data, "physicians may believe that off-label use of this agent is effective and outweighs the risks," they wrote. However, randomized trials suggest there is a risk of adverse events, including thromboembolism, Lin and colleagues noted.

To help clarify the issue, they performed a systematic review of the literature, looking for placebo-controlled studies that analyzed the effects of the compound in patients who did not have hemophilia. All told, they found 26 trials, including 14 that evaluated prophylactic use and 12 that looked at therapeutic use.

In a meta-analysis of the prophylactic trials -- preventing anticipated bleeding, during surgery, for example -- Lin and colleagues found "modest" benefits favoring the drug. Specifically:

Patients getting recombinant factor VIIa lost less blood than those on placebo. The weighted mean difference was minus 276 milliliters.

On the other hand, there was no significant difference in mortality; although the odds ratio was 0.82, favoring factor VIIa, the 95% confidence interval crossed unity, the researchers found.

There was a trend in favor of placebo in terms of the risk of thromboembolism, but it also did not reach significance.

For therapeutic use -- stopping existing bleeding -- Lin and colleagues found a decrease in the risk of death and an increase in the risk of thromboembolism, but neither was significant.

Nor was there any difference in control of bleeding or red blood cell transfusion, they reported.

The researchers noted that most of the 26 trials had "some potential threats to validity," mainly because of lack of detail in the published report. Plus, they wrote, most of the studies (eight prophylactic trials and all of the therapeutic studies) were either supported by the manufacturer of recombinant factor VIIa or were coauthored by an employee of the company.

Several studies had aspects that could not be included in the pooled analysis, they wrote, but they were unable to get additional data from the authors to allow them to be used. It is also not possible to exclude publication bias, they noted.

"Clinically significant benefits (of the drug) in patients without hemophilia remain unproven," the researchers concluded, and, given the risks, off-label use should only occur in clinical trials.

The study was supported by the UK National Health Service Blood and Transplant and by Canadian Blood Services. Lin reported being a site investigator for a registry on the off-label use of recombinant factor VIIa that is funded by an unrestricted educational grant from Novo Nordisk but she receives no payment for participation.

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